24 June 2011
The European Medicines Agency (EMA) has published an update on their ongoing benefit-risk review of pioglitazone▼–containing medicines and the occurrence of bladder cancer. The Committee for Medicinal Products for Human Use (CHMP) will finalise its review in July and make recommendations on the future use of these medicines then.
While the review is ongoing the CHMP is not recommending any changes to the use of pioglitazone-containing medicines. However, prescribers should be aware of this safety concern about bladder cancer, in addition to several other safety concerns with this drug (see below). Pioglitazone remains a black triangle drug and any suspected adverse reactions should be reported through the Yellow Card system.
Healthcare professionals should continue to follow NICE guidance on type 2 diabetes, which places pioglitazone generally as a third-line hypoglycaemic option for patients following metformin and a sulfonylurea. A previous NPC Rapid Review discusses its place in therapy following the withdrawal of rosiglitazone.
What is the background to this?
The risk of bladder cancer in association with pioglitazone has been under close review by the CHMP since 2000, and the manufacturer is conducting several cohort studies to investigate this concern. The three interim study reports have so far not confirmed a clear association between the use of pioglitazone and the occurrence of bladder cancer, but there is a signal of a potential increased risk in those with longest exposure and highest cumulative dose. The current review of pioglitazone-containing medicines was initiated in March 2011, following clinically relevant signals of the possibility of such an increased risk from spontaneous reports and various trial data.
The CHMP has discussed the French cohort study, which prompted the French Medicines Agency decision to suspend the use of pioglitazone-containing medicines in France earlier this month. They felt this study strengthened the signal of a small increased risk of bladder cancer, but that it had several methodological limitations, which could weaken its findings. It was subsequently reported that Germany had also suspended pioglitazone.
Overall, the Committee agreed that there were still numerous issues to be resolved before it could make recommendations on the future use of pioglitazone-containing medicines. They have referred the issue to the Scientific Advisory Group on Diabetes/Endocrinology to discuss in early July 2011. Following which, the CHMP will give its final opinion on the benefits and risks of these medicines.
This safety concern about a possible increased risk of bladder cancer with pioglitazone is in addition to previous safety concerns with this class of drugs. Rosiglitazone was withdrawn from clinical use across Europe in September 2010 because of concerns over excess cardiovascular risk. Pioglitazone remains an option but prescribers should be aware that this drug is not without safety issues. These were discussed in some detail in previous MeReC Rapid Reviews No. 2199 and 3909.
Briefly, there is consistent evidence that pioglitazone can cause weight gain and fluid retention, and lead to new or worsening heart failure. This is not a rare occurrence, and it can be serious and sometimes fatal. Pioglitazone is contraindicated in patients with heart failure or a history of heart failure. With regard to ischaemic heart disease, the majority of published studies do not suggest that there is an increased risk of ischaemic heart disease with pioglitazone, like there is with rosiglitazone. However, as head-to-head comparisons from prospective RCTs comparing the cardiovascular safety of rosiglitazone and pioglitazone are not available, we should still be cautious with pioglitazone use.
NICE advises that pioglitazone should not be commenced or continued in people with a higher risk of fracture, because it may increase this risk further. And recently, a meta-analysis has suggested that glitazones could be associated with an increased risk of pneumonia or lower respiratory tract infection.
As the recently published MeReC Bulletin on type 2 diabetes discusses in some detail, the preferred hypoglycaemic drugs recommended by NICE are metformin, a sulfonylurea and human NPH insulin. These interventions have been shown in randomised controlled trials to help patients live longer or better lives. Newer hypoglycaemic drugs, such as pioglitazone, may have a role in some individuals. However, as the withdrawal of rosiglitazone, and mounting safety concerns over pioglitazone, illustrate, their long term safety is not established, and robust evidence that they help patients live longer or better is not yet available. NICE guidance on type 2 diabetes places pioglitazone generally as a third-line hypoglycaemic option for patients following metformin and a sulfonylurea. But progression to triple blood glucose lowering therapy should not be automatic, and clinicians should discuss adherence and the risks and benefits of this approach with individual patients.
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